DESCRIPTION (adapted from the application) The long-term objectives of this application are to understand the regulation of genes expressed in the hypothalamus that encode anorectic and orexigenic peptides, and their interactions with the leptin-leptin receptor axis. This information will guide the study in rats of potential medical therapies for obesity, that will be translated to the study and treatment of human obesity. In Aim 1, the effect of the leptin receptor mutations, Lepr-fa-f ("Koletsky") and Lepr-fa ("Zucker"), on the hypothalamic expression of proopiomelanocortin (POMC, the gene which encodes the anorectic peptide alpha-MSH), agouti related protein (AGRP, a potent antagonist of alpha-MSH), and neuropeptide Y (NPY,an orexigenic peptide coexpressed in the same neurons as AGRP), will be studied within the same brain dissections using a very sensitive solution hybridization assay. The effect of gene dosage of Lepr-fa-f on neuroendocrine gene expression in the hypothalamus, body composition and leptin production per adipocyte will also be studied. The hypothesis that the administration of low dose leptin will reduce or eliminate the endocrine, metabolic and behavioral adjustments to reduced body weight will be tested in several Aims in both rodents and humans. In the rodent experiments, leptin will be co-administered with other known anorectic agents: sibutramine (a norepinephrine and serotonin reuptake inhibitor); naltrexone (an opioid receptor antagonist known to stimulate hypothalamic POMC expression); and pergolide (a dopamine agonist). In human experiments, low dose leptin will be co-administered with sibutramine, or administered after a period of 10 percent loss in body weight. The effects of these treatments on neuroendocrine gene expression, CSF levels of neuropeptides, energy homeostasis, and body composition will be analyzed. I plan an investigative career in academic medicine. Although my background in molecular research is fairly extensive, I have no formal experience in conducting clinical research and relevant statistical analysis. As part of my career development plan, I will enroll in courses at Columbia University in clinical research study design and statistics. In Aims 3 and 4, I will be part of ongoing clinical research projects, working closely with experienced investigators, while pursuing my own aspects of the projects. My sponsors, Dr. Leibel and Dr. Wardlaw, are experienced in basic and clinical research. They are easily accessible, enthusiastic about my projects, and will facilitate my transition to status as an independent investigator.